BACKGROUND: Osteoarthritis (OA) is a chronic progressive illness for which effective therapy is needed. We hypothesize that periarticular factors such as body fatness and muscle function are important determinants of mobility function, and also the development of knee OA, and that muscle function is compromised by local but not systemic inflammation. Basic Research: We conducted an ACUC approved experiment to determine the individual and combined effects of arthritis and hind-limb unloading on skeletal muscle function assessed by contractile force and by 31P NMR spectroscopy, and to also explore the associations between muscle function and local inflammatory mediators. Female 3-4 month old F344 rats were induced to develop (1) arthritis (CIA n= 9) by collagen injection; (2) muscle atrophy by hind-limb unloading (HU n= 7); (3) both arthritis and atrophy (CH n=5) and compared to (4) controls (CTL n=9). Animals underwent NMR spectroscopy to determine the [PCr/(PCr+Pi)] ratio reflective of muscle energy stores. This ratio during exercise and early recovery differed between the CIA and HU groups (p < 0.05). The CH group was the slowest to recover to baseline, and differed significantly from the HU group. Although the CIA and CH groups demonstrated force characteristics that did not differ significantly, differences were observed between CIA and HU groups (p < 0.05) (7). Blood and muscle samples acquired upon completion of the NMR procedure were tested for interleukins (IL)-1, -6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by ELISA (Biosource). Although right and left muscle cytokine levels were well correlated (r >0.70; p < 0.05), serum levels did not predict muscle levels of the above cytokines (8). Mean IFN-gamma level was significantly lower in the CIA (25.80 mcg/ml) and HU groups (81.62 mcg/ml) than CTLs (99.1 mcg/ml), and lowest in the CH group (17.49 mcg/ml). Mean IL-6 level was significantly lower in the combined CH group (16.96 mcg/ml) than CTLs (68.78 mcg/ml). The groups did not differ significantly with regard to serum cytokine levels. We conclude from this experiment that arthritis and atrophy result in bioenergetically, and immunologically distinct muscle characteristics. We also conclude that bioenergetic recovery from exercise is most impaired with combined arthritis and atrophy. These characteristics correspond to observed group differences in muscle, but not serum levels of IFN-gamma and IL-6. Epidemiologic Research: We analyzed the baseline data of the Women's Health and Aging Study to determine the relationship between knee osteoarthritis and mobility function in a cohort of high-functioning older women, and evaluate the contributions of muscle strength, body weight, and pain severity to these limitations. The 69 women classified as "symptomatic" for knee OA, 48 with "asymptomatic/intermittently symptomatic," knee OA, and 285 with "no knee OA" were included in the final analysis. Despite selection for their high level of self-reported function, performance was slower and task modification was more frequently reported among women with knee OA than women without knee OA. Lower knee extensor strength, higher body weight, and greater pain severity were associated with knee OA, and also with functional limitations. Conclusion. Knee OA appeared to be associated with early functional limitations in this cohort of high-functioning, older, community-resident women. Lower knee extensor strength, higher body weight, and pain severity were closely associated with these limitations. We published these results in the Journal of Rheumatology. Clinical Research Studies of knee OA: We embarked on 2 independent clinical studies in the past year to determine whether muscle strength, mass and function important determinants of mobility function in adults with knee OA, and if these characteristics are associated with inflammatory biomarkers. For the first study, we have begun recruitment of participants for a case-control study investigating inflammatory mediators of muscle malfunction that accompanies osteoarthritis of the knee. Thus far we have enrolled 14 participants, with recruitment that will resume at the ASTRA unit of Harbor Hospital. Although the results are still preliminary, participants with symptomatic osteoarthritis of the knee report greater pain and mobility difficulty, than adults without knee OA of comparable demographic characteristics and body size. OA participants also exhibited lower levels of physical activity, poorer mobility performance, and lower strength, with lower neuromuscular efficiency assessed by surface electromyography. Blood and muscle biopsy samples are being analyzed for inflammatory and OA-related biomarkers.The second study was done in collaboration with the Johns Hopkins University School of Nursing, we conducted a study to determine the feasibility and efficacy of a home-based neuromuscular electrical stimulation (NMES) treatment to the quadriceps femoris (QF) on muscle strength, physical activity, physical performance and pain severity in older adults with knee osteoarthritis (OA) beyond an arthritis self-management course (EDU) (n=34). The stimulated knee-extensor showed a 9.1% increase in isokinetic strength over the 12-week trial compared to a 7% loss in the EDU group (time X group interaction p=0.04). Mobility performance also improved in the NMES group compared to EDU, while severity of pain reported did not. From this study we conclude that muscle strength is an important determinant of mobility function in adults with knee OA, and that a home-based NMES is a feasible intervention capable of improving muscle strength and performance in adults with knee OA without exacerbating pain.